Oxycodone formulations

ABSTRACT

The invention is directed to sustained release formulations containing oxycodone or a pharmaceutically acceptable salt thereof which provide a mean C 24 /C max  oxycodone ratio of 0.6 to 1.0 or 0.7 to 1 after oral administration at steady state to patients and methods thereof.

This application is a divisional of U.S. Ser. No. 14/665,715, filed Mar.23, 2015, which is a continuation of U.S. Ser. No. 14/548,435, filed onNov. 20, 2014, which is a continuation of U.S. Ser. No. 12/917,148,filed on Nov. 1, 2010, which is a continuation of U.S. Ser. No.10/476,409, filed on Apr. 15, 2004, now U.S. Pat. No. 7,846,476, whichis a 371 of International Application No. PCT/US02/14024, filed on May2, 2002, which claims the benefit of U.S. Provisional Application No.60/288,211, filed May 2, 2001, the disclosures of are herebyincorporated by reference.

FIELD OF THE INVENTION

The invention is directed to sustained release formulations containingoxycodone or a pharmaceutically acceptable salt thereof which issuitable for administration to a patient.

BACKGROUND OF THE INVENTION

Once-a-day sustained release opioid formulations are disclosed in U.S.Pat. Nos. 5,478,577; 5,672,360; 5,958,459; 6,103,261; 6,143,332;5,965,161; 5,958,452 and 5,968,551. All documents cited herein,including the foregoing, are incorporated by reference in theirentireties for all purposes.

SUMMARY AND OBJECTS OF THE INVENTION

It is an object of the present invention to provide an oxycodoneformulation suitable for once daily administration for effective painmanagement.

It is an object of preferred embodiments of the present invention toprovide a pharmaceutically acceptable dosage form for orallyadministering oxycodone to provide analgesic therapy beyond itsrelatively short half-life over an extended period of time, and having aduration of pain relief of at least 24-hours.

The above objects and others are attained by the present invention,which is directed to a dosage form comprising an analgesically effectiveamount of oxycodone or a pharmaceutically acceptable salt thereof and asustained release material, the dosage form providing an analgesiceffect for at least about 24 hours after oral administration at steadystate to human patients; and the dosage form providing a meanC₂₄/C_(max) oxycodone ratio of 0.6 to 1.0 after oral administration atsteady state to the patients.

In certain embodiments of the invention, the dosage form afteradministration to patients provides a mean T_(max) of oxycodone in-vivowhich occurs at about 2 to about 17 hours (e.g., about 2 to about 8hours) after administration at steady state of the dosage form.

In certain embodiments of the invention, the mean T_(max) of oxycodonein-vivo occurs at about 6.5 hours to about 17 hours, at about 8 to about16 hours, at about 10 to about 16 hours, or at about 12 to about 16hours after administration at steady state of the dosage form.

In certain embodiments of the invention, the dosage form provides ananalgesic effect for at least about 24 hours after administration of thedosage form to human patients at steady state; and provides a meanC₂₄/C_(max) oxycodone ratio of 0.60 to 1.0 after administration atsteady state to patients.

In certain embodiments of the invention, the dosage form provides ananalgesic effect for at least about 24 hours after administration atsteady state to human patients; and provides a mean C₂₄/C_(max)oxycodone ratio of 0.60 to 1.0 or 0.7 to 1.0 after administration atsteady state to patients. In certain embodiments of the invention, thedosage form provides an in-vitro release rate, of oxycodone or apharmaceutically acceptable salt thereof, when measured by the USPBasket Method at 100 rpm in 900 ml aqueous buffer at a pH of between 1.6and 7.2 at 37° C. of from 0% to about 40% at 1 hour, from about 8% toabout 70% at 4 hours, from about 20% to about 80% at 8 hours, from about30% to about 95% at 12 hours, from about 35% to about 95% at 18 hours,and greater than about 50% at 24 hours.

In certain preferred embodiments the sustained release oral dosage formof the present invention provides oxycodone plasma levels which areeffective for 24 hourly dosing, characterized by a W₅₀ for the oxycodoneof between 4 and 24 hours after administration at steady state. Incertain embodiments, the W₅₀ is at least 4 hours, preferably at least 12hours, and more preferably at least 18 hours, after administration atsteady state.

In certain embodiments the sustained release oral dosage form of thepresent invention comprises a matrix which includes a sustained releasematerial and oxycodone or a pharmaceutically acceptable salt thereof. Incertain embodiments, the matrix is compressed into a tablet and may beoptionally overcoated with a coating that in addition to the sustainedrelease material of the matrix may control the release of the oxycodoneor pharmaceutically acceptable salt thereof from the formulation, suchthat blood levels of active ingredient are maintained within thetherapeutic range over an extended period of time. In certain alternateembodiments, the matrix is encapsulated.

In certain embodiments, the sustained release oral dosage form of thepresent invention comprises a plurality of pharmaceutically acceptablesustained release matrices comprising oxycodone or a pharmaceuticallyacceptable salt thereof, the dosage form maintaining the blood plasmalevels of oxycodone within the therapeutic range over an extended periodof time when administered to patients.

Preferably, the formulations prepared in accordance with the presentinvention can be presented in tablet, capsule, or in any other suitableunit dosage form.

In certain embodiments the sustained release oral dosage form of thepresent invention is an osmotic dosage form which comprises a singlelayer or bilayer core comprising oxycodone or a pharmaceuticallyacceptable salt thereof; an expandable polymer; a semipermeable membranesurrounding the core; and a passageway disposed in the semipermeablemembrane for sustained release of the oxycodone or pharmaceuticallyacceptable salt thereof, such that blood levels of active ingredient aremaintained within the therapeutic range over an extended period of timewhen administered to patients.

In certain embodiments the sustained release oral dosage form of thepresent invention comprises a substantially homogenous core comprisingoxycodone or a pharmaceutically acceptable salt thereof and anexpandable polymer; a semipermeable membrane surrounding the core; and apassageway disposed in the semipermeable membrane for sustained releaseof the oxycodone or pharmaceutically acceptable salt thereof, such thatblood levels of active ingredient are maintained within the therapeuticrange over an extended period of time when administered to a patients.

In certain embodiments of the present invention, there is provided amethod of treating pain associated conditions in patients requiring suchtreatment which method includes administering to a patient an effectiveamount of oxycodone or a pharmaceutically acceptable salt thereof in asustained release dosage form as described herein.

In certain embodiments, the invention is directed to the use of asustained release dosage form comprising a pharmaceutically acceptablematrix comprising oxycodone or a pharmaceutically acceptable saltthereof and a sustained release material in the production of ananalgesic preparation for oral administration to human patients on aonce a day basis, to provide an analgesic effect for at least about 24hours and a mean C₂₄/C_(max) oxycodone ratio of 0.6 to 1.0 afteradministration at steady state to said patients.

In certain embodiments, the invention is directed to the use of asustained release oral dosage form comprising a bilayer core comprisinga drug layer comprising an analgesically effective amount of oxycodoneor a pharmaceutically acceptable salt thereof; and a displacement layercomprising an osmopolymer; and a semipermeable wall surrounding thebilayer core having a passageway disposed therein for the release ofsaid oxycodone or pharmaceutically acceptable salt thereof; in theproduction of an analgesic preparation for oral administration to humanpatients to provide an analgesic effect at least about 24 hours afteroral administration at steady state to human patients; and to provide amean C₂₄/C_(max) oxycodone ratio of 0.6 to 1.0 after administration atsteady state to said patients.

In certain embodiments, the invention is directed to the use of asustained release dosage form comprising a plurality of sustainedrelease matrices comprising oxycodone or a pharmaceutically acceptablesalt thereof and a sustained release material, in the production of ananalgesic preparation for oral administration to a patient on aonce-a-day basis, to provide an analgesic effect for at least 24 hoursafter oral administration at steady state to human patients; and toprovide a mean C₂₄/C_(max) oxycodone ration of 0.6 to 1.0 after oraladministration at steady state to said patients.

The term “C_(max)” as it is used herein is the highest plasmaconcentration of the drug attained within the dosing interval.

The term “C₂₄” as it is used herein is the plasma concentration of thedrug at 24 hours after administration.

The term “T_(max)” as it is used herein is the time period which elapsesafter administration of the dosage form until the plasma concentrationof the drug attains the highest plasma concentration within the dosinginterval.

The term “W₅₀” for purposes of the present invention is the durationover which the plasma concentrations are equal to or greater than 50% ofthe peak concentration. The parameter is determined by linearinterpolation of the observed data and represents the difference in timebetween the first (or only) upslope crossing and the last (or only)downslope crossing in the plasma profile.

The term “C₂₄/C_(max) ratio” is defined for purposes of the presentinvention as the ratio of the plasma concentration of the drug at 24hours after administration to the highest plasma concentration of thedrug attained within the dosing interval.

The term “USP Basket Method” is the Basket Method described in U.S.Pharmacopoeia XXII (1990), herein incorporated by reference.

The term “steady state” means that the amount of the drug reaching thesystem is approximately the same as the amount of the drug leaving thesystem. Thus, at “steady-state”, the patient's body eliminates the drugat approximately the same rate that the drug becomes available to thepatient's system through absorption into the blood stream.

The term “semipermeable wall” for purposes of the present inventionmeans that the wall is permeable to the passage of an exterior fluid,such as aqueous or biological fluid, in the environment of use,including the gastrointestinal tract, but impermeable to drug.

The term “expandable polymer” for purposes of the present inventionmeans a polymer which upon exposure to an aqueous or biological fluid,absorbs the fluid resulting in a greater mass.

The term “mean” for purposes of the present invention, when used todefine a pharmacokinetic value (e.g., T_(max)) represents the arithmeticmean value measured across a patient population.

The phrase “pharmaceutically acceptable salt” includes, but is notlimited to, metal salts such as sodium salt, potassium salt, cesium saltand the like; alkaline earth metals such as calcium salt, magnesium saltand the like; organic amine salts such as triethylamine salt, pyridinesalt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, fumarate, tartrate and the like; sulfonatessuch as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and thelike; amino acid salts such as arginate, asparginate, glutamate and thelike.

DESCRIPTION OF THE INVENTION

In certain embodiments of the present invention, the sustained releasedosage form provides an in-vitro release rate of oxycodone or apharmaceutically acceptable salt thereof, when measured by the USPBasket Method at 100 rpm in 900 ml aqueous buffer at a pH of between 1.6and 7.2 at 37° C. of from 0% to about 40% at 1 hour, from about 8% toabout 70% at 4 hours, from about 20% to about 80% at 8 hours, from about30% to about 95% at 12 hours, from about 35% to about 95% at 18 hrs, andgreater than about 50% at 24 hours.

In certain embodiments of the present invention the time period duringwhich oxycodone blood levels (after administration at steady state) aregreater than or equal to 75% of the maximum blood level (T_(≧0.75Cmax))may be 4 hours or greater, preferably 6 hours or greater.

In certain embodiments, the time at which oxycodone blood levels reachtheir maximum concentration (T_(max)) is about 2 to about 17 hours,preferably about 6.5 hours to about 17 hours, more preferably about 8 toabout 16 hours, and even more preferably about 10 to about 16 or about12 to about 16 hours after administration at steady state of the dosageform.

In certain embodiments of the present invention, the dosage formprovides a C₂₄/C_(max) ratio after administration at steady state of 0.6to 1.0, a ratio 0.7 to 0.99 or a ratio of 0.8 to 0.95. In otherembodiments of the present invention, the dosage form provides aC₂₄/C_(max) ratio after administration at steady state of 0.7 to 1.0, aratio 0.72 to 0.99 or a ratio of 0.74 to 0.95.

In certain embodiments of the present invention, the dosage formprovides a C₂₄/C_(max) ratio after administration at steady state of 0.6to 1.0, a ratio 0.7 to 0.99 or a ratio of 0.8 to 0.95 and a (T_(max)) ofabout 6.5 hours to about 17 hours, about 8 to about 16 hours, about 10to about 16 hours or about 12 hours to about 16 hours. In otherembodiments of the present invention, the dosage form provides aC₂₄/C_(max) ratio after administration at steady state of 0.7 to 1.0, aratio 0.72 to 0.99 or a ratio of 0.74 to 0.95 and a (T_(max)) in about 2to about 17 hours.

In certain embodiments of the present invention, the co-administrationof food will not significantly increase or decrease the extent ofoxycodone absorption.

The sustained release oral dosage form of the present invention includesfrom about 1 to about 640 mg of oxycodone or a pharmaceuticallyacceptable salt thereof (e.g., oxycodone hydrochloride). Preferably thesustained release oral dosage form of the present invention includesfrom about 5 to about 500 mg oxycodone or a pharmaceutically acceptablesalt thereof, more preferably from about 10 to about 320 mg oxycodone ora pharmaceutically acceptable salt thereof and even more preferably fromabout 10 to about 160 mg oxycodone or a pharmaceutically acceptable saltthereof.

In other preferred embodiments, the sustained release dosage form of thepresent invention comprises from about 10 to about 160 mg oxycodonehydrochloride or an equivalent amount of oxycodone or a pharmaceuticallyacceptable salt thereof other than the hydrochloride salt.

The present invention includes a method for administering from about 1to about 640 mg of oxycodone or a pharmaceutically acceptable saltthereof on a once-a-day basis to a patient in need of relief of pain, inaccordance with the pharmacokinetic parameters disclosed herein.Preferably, the method includes administering from about 5 to about 500mg oxycodone or a pharmaceutically acceptable salt thereof.

The method of administration according to the present invention isparticularly applicable to the treatment of acute and chronic pain,particularly pain associated with terminal disease such as cancer;chronic backpain; and post-operative pain.

Dosage Forms

In certain embodiments the oral dosage form includes a sustained-releasematerial which is incorporated into a matrix along with the oxycodone orpharmaceutically acceptable salt thereof to provide for the sustainedrelease of the oxycodone. The sustained-release material may behydrophobic or hydrophilic as desired. The oral dosage form of thepresent invention may be prepared as granules, spheroids, matrixmultiparticulates, etc. which comprise oxycodone or a pharmaceuticallyacceptable salt thereof in a sustained release matrix, which may becompressed into a tablet or encapsulated. The oral dosage form of thepresent invention may optionally include other pharmaceuticallyacceptable ingredients (e.g., diluents, binders, colorants, lubricants,etc.).

In certain embodiments, the oral dosage form of the present inventionmay be an osmotic dosage form having a push or displacement compositionas one of the layers of a bilayer core for pushing oxycodone or apharmaceutically acceptable salt thereof from the dosage form, and asemipermeable wall composition surrounding the core, wherein the wallhas at least one exit means or passageway for delivering the oxycodonefrom the dosage form. Alternatively, the core of the osmotic dosage formmay comprise a single layer core including a controlled release polymerand oxycodone or a pharmaceutically acceptable salt thereof.

Preferably the dosage forms of the present invention provide ananalgesic effect for at least about 24 hours after administration.

Sustained-Release Matrix Formulations

In one preferred embodiment of the present invention, the sustainedrelease carrier may be incorporated into a matrix with the oxycodone orpharmaceutically acceptable salt thereof which matrix provides for thesustained release of the oxycodone.

A non-limiting list of suitable sustained-release materials which may beincluded in a sustained-release matrix according to the inventioninclude hydrophilic and/or hydrophobic materials, such as gums,cellulose ethers, acrylic resins, protein derived materials, waxes,shellac, and oils such as hydrogenated castor oil and hydrogenatedvegetable oil. However, any pharmaceutically acceptable hydrophobic orhydrophilic sustained-release material which is capable of impartingsustained-release of the oxycodone or pharmaceutically acceptable saltthereof may be used in accordance with the present invention. Preferredsustained-release polymers include alkylcelluloses such asethylcellulose, acrylic and methacrylic acid polymers and copolymers;and cellulose ethers, especially hydroxyalkylcelluloses (especiallyhydroxypropylmethylcellulose) and carboxyalkylcelluloses. Preferredacrylic and methacrylic acid polymers and copolymers include methylmethacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates,ethyl acrylate, trimethyl ammonioethyl methacrylate, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. Certain preferred embodiments utilizemixtures of any of the foregoing sustained-release materials in thematrix of the invention.

The matrix also may include a binder. In such embodiments, the binderpreferably contributes to the sustained-release of the oxycodone orpharmaceutically acceptable salt thereof from the sustained-releasematrix.

If an additional hydrophobic binder material is included, it ispreferably selected from natural and synthetic waxes, fatty acids, fattyalcohols, and mixtures of the same. Examples include beeswax, carnaubawax, stearic acid and stearyl alcohol. This list is not meant to beexclusive. In certain preferred embodiments, a combination of two ormore hydrophobic binder materials are included in the matrixformulations.

Preferred hydrophobic binder materials which may be used in accordancewith the present invention include digestible, long chain (C₈-C₅₀,especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such asfatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils, natural and synthetic waxes and polyalkylene glycols.Hydrocarbons having a melting point of between 25° and 90° C. arepreferred. Of the long-chain hydrocarbon binder materials, fatty(aliphatic) alcohols are preferred in certain embodiments. The oraldosage form may contain up to 80% (by weight) of at least onedigestible, long chain hydrocarbon.

In certain embodiments, the hydrophobic binder material may comprisenatural or synthetic waxes, fatty alcohols (such as lauryl, myristyl,stearyl, cetyl or preferably cetostearyl alcohol), fatty acids,including but not limited to fatty acid esters, fatty acid glycerides(mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons,normal waxes, stearic acid, stearyl alcohol and hydrophobic andhydrophilic materials having hydrocarbon backbones. Suitable waxesinclude, for example, beeswax, glycowax, castor wax and carnauba wax.For purposes of the present invention, a wax-like substance is definedas any material which is normally solid at room temperature and has amelting point of from about 30 to about 100° C. In certain preferredembodiments, the dosage form comprises a sustained release matrixcomprising oxycodone or a pharmaceutically acceptable salt thereof andat least one water soluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆,preferably C₁₄-C₂₂, aliphatic alcohol and, optionally, at least onepolyalkylene glycol. The hydroxyalkyl cellulose is preferably a hydroxy(C₁ to C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose.The amount of the at least one hydroxyalkyl cellulose in the presentoral dosage form may be determined, inter alia, by the precise rate ofoxycodone or oxycodone salt release required. The aliphatic alcohol maybe, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of the aliphatic alcohol in the presentoral dosage form may be determined, as above, by the precise rate ofoxycodone or oxycodone salt release required. It may also depend onwhether at least one polyalkylene glycol is present in or absent fromthe oral dosage form. In the absence of at least one polyalkyleneglycol, the oral dosage form preferably contains between about 20% andabout 50% (by wt) of the aliphatic alcohol. When a polyalkylene glycolis present in the oral dosage form, then the combined weight of thealiphatic alcohol and the polyalkylene glycol preferably constitutesbetween about 20% and about 50% (by wt) of the total dosage form.

In one preferred embodiment, the ratio of, e.g., the at least onehydroxyalkyl cellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the oxycodone or oxycodone salt from the formulation. Incertain embodiments, a ratio of the hydroxyalkyl cellulose to thealiphatic alcohol/polyalkylene glycol of between 1:1 and 1:4 ispreferred, with a ratio of between 1:2 and 1:3 being particularlypreferred.

In certain embodiments, the polyalkylene glycol may be, for example,polypropylene glycol, or polyethylene glycol which is preferred. Theaverage molecular weight of the at least one polyalkylene glycol ispreferably between 1,000 and 15,000, especially between 1,500 and12,000.

Another suitable sustained-release matrix comprises an alkylcellulose(especially ethylcellulose), a C₁₂ to C₃₆ aliphatic alcohol and,optionally, a polyalkylene glycol.

In addition to the above ingredients, a sustained-release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

In order to facilitate the preparation of a solid, sustained-releaseoral dosage form according to this invention there is provided, in afurther aspect of the present invention, a process for the preparationof a solid, sustained-release oral dosage form according to the presentinvention comprising incorporating oxycodone or a salt thereof in asustained-release matrix. Incorporation in the matrix may be effected,for example, by:

(a) forming granules comprising at least one hydrophobic and/orhydrophilic material as set forth above (e.g., a water solublehydroxyalkyl cellulose) together with the oxycodone or pharmaceuticallyacceptable salt thereof;

(b) mixing the at least one hydrophobic and/or hydrophilicmaterial-containing granules with at least one C₁₂-C₃₆ aliphaticalcohol, and

(c) optionally, compressing and shaping the granules.

The granules may be formed by any of the procedures well-known to thoseskilled in the art of pharmaceutical formulation. For example, in onepreferred method, the granules may be formed by wet granulatinghydroxyalkyl cellulose/oxycodone or oxycodone salt with water. In aparticularly preferred embodiment of this process, the amount of wateradded during the wet granulation step is preferably between 1.5 and 5times, especially between 1.75 and 3.5 times, the dry weight of theoxycodone or oxycodone salt.

A sustained-release matrix can also be prepared by, e.g.,melt-granulation or melt-extrusion techniques. Generally,melt-granulation techniques involve melting a normally solid hydrophobicbinder material, e.g., a wax, and incorporating a powdered drug therein.To obtain a sustained release dosage form, it may be necessary toincorporate a hydrophobic sustained-release material, e.g.ethylcellulose or a water-insoluble acrylic polymer, into the molten waxhydrophobic binder material. Examples of sustained-release formulationsprepared via melt-granulation techniques are found, e.g., in U.S. Pat.No. 4,861,598.

The additional hydrophobic binder material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve sustained release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like binder substances may be those with awater-solubility that is lower than about 1:5,000 (w/w).

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theoxycodone or pharmaceutically acceptable salt thereof, together with asustained release material and preferably a binder material to obtain ahomogeneous mixture. The homogeneous mixture is then heated to atemperature sufficient to at least soften the mixture sufficiently toextrude the same. The resulting homogeneous mixture is then extruded,e.g., using a twin-screw extruder, to form strands. The extrudate ispreferably cooled and cut into multiparticulates by any means known inthe art. The matrix multiparticulates are then divided into unit doses.The extrudate preferably has a diameter of from about 0.1 to about 5 mmand provides sustained release of the oxycodone or pharmaceuticallyacceptable salt thereof for a time period of at least about 24 hours.

An optional process for preparing the melt extruded formulations of thepresent invention includes directly metering into an extruder ahydrophobic sustained release material, the oxycodone or salt thereof,and an optional binder material; heating the homogenous mixture;extruding the homogenous mixture to thereby form strands; cooling thestrands containing the homogeneous mixture; cutting the strands intomatrix multiparticulates having a size from about 0.1 mm to about 12 mm;and dividing said particles into unit doses. In this aspect of theinvention, a relatively continuous manufacturing procedure is realized.

Plasticizers, such as those described above, may be included inmelt-extruded matrices. The plasticizer is preferably included as fromabout 0.1 to about 30% by weight of the matrix. Other pharmaceuticalexcipients, e.g., talc, mono or poly saccharides, colorants, flavorants,lubricants and the like may be included in the sustained releasematrices of the present invention as desired. The amounts included willdepend upon the desired characteristic to be achieved.

The diameter of the extruder aperture or exit port can be adjusted tovary the thickness of the extruded strands. Furthermore, the exit partof the extruder need not be round; it can be oblong, rectangular, etc.The exiting strands can be reduced to particles using a hot wire cutter,guillotine, etc.

A melt extruded matrix multiparticulate system can be, for example, inthe form of granules, spheroids or pellets depending upon the extruderexit orifice. For purposes of the present invention, the terms“melt-extruded matrix multiparticulate(s)” and “melt-extruded matrixmultiparticulate system(s)” and “melt-extruded matrix particles” shallrefer to a plurality of units, preferably within a range of similar sizeand/or shape and containing one or more active agents and one or moreexcipients, preferably including a hydrophobic sustained releasematerial as described herein. Preferably the melt-extruded matrixmultiparticulates will be of a range of from about 0.1 to about 12 mm inlength and have a diameter of from about 0.1 to about 5 mm. In addition,it is to be understood that the melt-extruded matrix multiparticulatescan be any geometrical shape within this size range. In certainembodiments, the extrudate may simply be cut into desired lengths anddivided into unit doses of the therapeutically active agent without theneed of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared that includean effective amount of melt-extruded matrix multiparticulates within acapsule. For example, a plurality of the melt-extruded matrixmultiparticulates may be placed in a gelatin capsule in an amountsufficient to provide an effective sustained release dose when ingestedand contacted by gastrointestinal fluid.

In another embodiment, a suitable amount of the multiparticulateextrudate is compressed into an oral tablet using conventional tabletingequipment using standard techniques. Techniques and compositions formaking tablets (compressed and molded), capsules (hard and soft gelatin)and pills are also described in Remington's Pharmaceutical Sciences,(Arthur Osol, editor), 1553-1593 (1980).

In yet another preferred embodiment, the extrudate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.).

Optionally, the sustained-release matrix multiparticulate systems,tablets, or capsules can be coated with a sustained release coating suchas the sustained release coatings described herein. Such coatingspreferably include a sufficient amount of hydrophobic and/or hydrophilicsustained-release material to obtain a weight gain level from about 2 toabout 25 percent, although the overcoat may be greater depending upon,e.g., the desired release rate.

The dosage forms of the present invention may further includecombinations of melt-extruded matrix multiparticulates containingoxycodone or pharmaceutically acceptable salt thereof. Furthermore, thedosage forms can also include an amount of an immediate releasetherapeutically active oxycodone or pharmaceutically acceptable saltthereof for prompt therapeutic effect. The immediate release oxycodoneor pharmaceutically acceptable salt thereof may be incorporated, e.g.,as separate multiparticulates within a gelatin capsule, or may be coatedon the surface of, e.g., melt extruded matrix multiparticulates.

The sustained-release profile of the melt-extruded formulations of theinvention can be altered, for example, by varying the amount ofsustained-release material, by varying the amount of plasticizerrelative to other matrix constituents, by varying the amount ofhydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc.

In other embodiments of the invention, melt-extruded formulations areprepared without the inclusion of the oxycodone or pharmaceuticallyacceptable salt thereof, which is added thereafter to the extrudate.Such formulations typically will have the oxycodone or pharmaceuticallyacceptable salt thereof blended together with the extruded matrixmaterial, and then the mixture would be tableted in order to provide aslow release formulation. Such formulations may be advantageous, forexample, when the therapeutically active agent included in theformulation is sensitive to temperatures needed for softening thehydrophobic material and/or the retardant material.

Typical melt-extrusion production systems suitable for use in accordancewith the present invention include a suitable extruder drive motorhaving variable speed and constant torque control, start-stop controls,and ammeter. In addition, the production system will include atemperature control console which includes temperature sensors, coolingmeans and temperature indicators throughout the length of the extruder.In addition, the production system will include an extruder such as atwin-screw extruder which consists of two counter-rotating intermeshingscrews enclosed within a cylinder or barrel having an aperture or die atthe exit thereof. The feed materials enter through a feed hopper and aremoved through the barrel by the screws and are forced through the dieinto strands which are thereafter conveyed such as by a continuousmovable belt to allow for cooling and being directed to a pelletizer orother suitable device to render the extruded ropes into the matrixmultiparticulate system. The pelletizer can consist of rollers, fixedknife, rotating cutter and the like. Suitable instruments and systemsare available from distributors such as C.W. Brabender Instruments, Inc.of South Hackensack, N.J. Other suitable apparatus will be apparent tothose of ordinary skill in the art.

A further aspect of the invention is related to the preparation ofmelt-extruded matrix multiparticulates as set forth above in a mannerwhich controls the amount of air included in the extruded product. Bycontrolling the amount of air included in the extrudate, the releaserate of the oxycodone or therapeutically acceptable salt thereof may bealtered.

Thus, in a further aspect of the invention, the melt-extruded product isprepared in a manner which substantially excludes air during theextrusion phase of the process. This may be accomplished, for example,by using a Leistritz extruder having a vacuum attachment. The extrudedmatrix multiparticulates prepared according to the invention using theLeistritz extruder under vacuum provides a melt-extruded product havingdifferent physical characteristics. In particular, the extrudate issubstantially non-porous when magnified, e.g., using a scanning electronmicroscope which provides an SEM (scanning electron micrograph). Suchsubstantially non-porous formulations may provide a faster release ofthe therapeutically active agent, relative to the same formulationprepared without vacuum. SEMs of the matrix multiparticulates preparedusing an extruder under vacuum appear very smooth, and themultiparticulates tend to be more robust than those multiparticulatesprepared without vacuum. It has been observed that in at least certainformulations, the use of extrusion under vacuum provides an extrudedmatrix multiparticulate product which is more pH-dependent than itscounterpart formulation prepared without vacuum.

Alternatively, the melt-extruded product is prepared using aWerner-Pfleiderer twin screw extruder.

In certain embodiments, a spheronizing agent is added to a granulate ormatrix multiparticulate and then spheronized to produce sustainedrelease spheroids. The spheroids are then optionally overcoated with asustained release coating by methods such as those described above.

Spheronizing agents which may be used to prepare the matrixmultiparticulate formulations of the present invention include anyart-known spheronizing agent. Cellulose derivatives are preferred, andmicrocrystalline cellulose is especially preferred. A suitablemicrocrystalline cellulose is, for example, the material sold as AvicelPH 101 (TradeMark, FMC Corporation). The spheronizing agent ispreferably included as about 1 to about 99% of the matrixmultiparticulate by weight.

In certain embodiments, in addition to the active ingredient andspheronizing agent, the spheroids may also contain a binder. Suitablebinders, such as low viscosity, water soluble polymers, will be wellknown to those skilled in the pharmaceutical art. However, water solublehydroxy lower alkyl cellulose, such as hydroxy propyl cellulose, arepreferred. Additionally (or alternatively) the spheroids may contain awater insoluble polymer, especially an acrylic polymer, an acryliccopolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethylcellulose.

In certain embodiments, a sustained release coating is applied to thesustained release spheroids, granules, or matrix multiparticulates. Insuch embodiments, the sustained-release coating may include a waterinsoluble material such as (a) a wax, either alone or in admixture witha fatty alcohol; or (b) shellac or zein. The coating is preferablyderived from an aqueous dispersion of the hydrophobic sustained releasematerial.

In certain embodiments, it is necessary to overcoat the sustainedrelease spheroids, granules, or matrix multiparticulates comprising theoxycodone or pharmaceutically acceptable salt thereof and sustainedrelease carrier with a sufficient amount of the aqueous dispersion of,e.g., alkylcellulose or acrylic polymer, to obtain a weight gain levelfrom about 2 to about 50%, e.g., about 2 to about 25%, in order toobtain a sustained-release formulation. The overcoat may be lesser orgreater depending upon, e.g., the desired release rate, the inclusion ofplasticizer in the aqueous dispersion and the manner of incorporation ofthe same. Cellulosic materials and polymers, including alkylcelluloses,are sustained release materials well suited for coating the sustainedrelease spheroids, granules, or matrix multiparticulates according tothe invention. Simply by way of example, one preferred alkylcellulosicpolymer is ethylcellulose, although the artisan will appreciate thatother cellulose and/or alkylcellulose polymers may be readily employed,singly or in any combination, as all or part of a hydrophobic coatingaccording to the invention.

One commercially available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly to the sustainedrelease spheroids, granules, or matrix multiparticulates.

In other preferred embodiments of the present invention, the sustainedrelease material comprising the sustained-release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate,poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), polymethacrylate, poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), and glycidyl methacrylatecopolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers Ammonio methacrylatecopolymers are well known in the art, and are described in the NationalFormulary (NF) XVII as fully polymerized copolymers of acrylic andmethacrylic acid esters with a low content of quaternary ammoniumgroups. In order to obtain a desirable dissolution profile, it may benecessary to incorporate two or more ammonio methacrylate copolymershaving differing physical properties, such as different molar ratios ofthe quaternary ammonium groups to the neutral (meth) acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Röhm GMBH andCo. Kg Darmstadt, Germany. There are several different types ofEudragit®. For example, Eudragit E is an example of a methacrylic acidcopolymer which swells and dissolves in acidic media. Eudragit L is amethacrylic acid copolymer which does not swell at about pH<5.7 and issoluble at about pH>6. Eudragit S does not swell at about pH<6.5 and issoluble at about pH>7. Eudragit RL and Eudragit RS are water swellable,and the amount of water absorbed by these polymers is pH-dependent;however, dosage forms coated with Eudragit RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from Rohmunder the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively.Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic andmethacrylic esters with a low content of quaternary ammonium groups, themolar ratio of ammonium groups to the remaining neutral (meth)acrylicesters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. Themean molecular weight is about 150,000. The code designations RL (highpermeability) and RS (low permeability) refer to the permeabilityproperties of these agents. Eudragit® RL/RS mixtures are insoluble inwater and in digestive fluids. However, coatings formed from the sameare swellable and permeable in aqueous solutions and digestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain asustained-release formulation having a desirable dissolution profile.Desirable sustained-release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L. Inembodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic sustained release material, theinclusion of an effective amount of a plasticizer in the aqueousdispersion of hydrophobic material will further improve the physicalproperties of the sustained-release coating. For example, becauseethyl-cellulose has a relatively high glass transition temperature anddoes not form flexible films under normal coating conditions, it ispreferable to incorporate a plasticizer into an ethylcellulose coatingcontaining sustained-release coating before using the same as a coatingmaterial. Generally, the amount of plasticizer included in a coatingsolution is based on the concentration of the film-former, e.g., mostoften from about 1 to about 50 percent by weight of the film-former.Concentration of the plasticizer, however, can only be properlydetermined after careful experimentation with the particular coatingsolution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

In certain embodiments, the uncoated/coated sustained release spheroids,granules, or matrix multiparticulates containing the oxycodone oroxycodone salt are cured until an endpoint is reached at which thesustained release spheroids, granules, or matrix multiparticulatesprovide a stable dissolution. The curing endpoint may be determined bycomparing the dissolution profile (curve) of the dosage form immediatelyafter curing to the dissolution profile (curve) of the dosage form afterexposure to accelerated storage conditions of, e.g., at least one monthat a temperature of 40° C. and a relative humidity of 75%. Curedformulations are described in detail in U.S. Pat. Nos. 5,273,760;5,286,493; 5,500,227; 5,580,578; 5,639,476; 5,681,585; and 6,024,982.Other examples of sustained-release formulations and coatings which maybe used in accordance with the present invention include U.S. Pat. Nos.5,324,351; 5,356,467; and 5,472,712.

In addition to the above ingredients, the spheroids, granules, or matrixmultiparticulates may also contain suitable quantities of othermaterials, e.g., diluents, lubricants, binders, granulating aids,colorants, flavorants and glidants that are conventional in thepharmaceutical art in amounts up to about 50% by weight of theformulation if desired. The quantities of these additional materialswill be sufficient to provide the desired effect to the desiredformulation.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein.

It has further been found that the addition of a small amount of talc tothe sustained release coating reduces the tendency of the aqueousdispersion to stick during processing, and acts as a polishing agent.

Sustained Release Osmotic Dosage

Sustained release dosage forms according to the present invention mayalso be prepared as osmotic dosage formulations. The osmotic dosageforms preferably include a bilayer core comprising a drug layer and adelivery or push layer, wherein the bilayer core is surrounded by asemipermeable wall and optionally having at least one passagewaydisposed therein.

The expression “passageway” as used for the purpose of this invention,includes aperture, orifice, bore, pore, porous element through whichoxycodone or oxycodone salt can be pumped, diffuse or migrate through afiber, capillary tube, porous overlay, porous insert, microporousmember, or porous composition. The passageway can also include acompound that erodes or is leached from the wall in the fluidenvironment of use to produce at least one passageway. Representativecompounds for forming a passageway include erodible poly(glycolic) acid,or poly(lactic) acid in the wall; a gelatinous filament; awater-removable poly(vinyl alcohol); leachable compounds such asfluid-removable pore-forming polysaccharides, acids, salts or oxides. Apassageway can be formed by leaching a compound from the wall, such assorbitol, sucrose, lactose, maltose, or fructose, to form asustained-release dimensional pore-passageway. The passageway can haveany shape, such as round, triangular, square and elliptical, forassisting in the sustained metered release of oxycodone or oxycodonesalt from the dosage form. The dosage form can be manufactured with oneor more passageways in spaced-apart relation on one or more surfaces ofthe dosage form. A passageway and equipment for forming a passageway aredisclosed in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064 and4,088,864. Passageways comprising sustained-release dimensions sized,shaped and adapted as a releasing-pore formed by aqueous leaching toprovide a releasing-pore of a sustained-release rate are disclosed inU.S. Pat. Nos. 4,200,098 and 4,285,987.

In certain embodiments, the bilayer core comprises a drug layer withoxycodone or a salt thereof and a displacement or push layer. In certainembodiments the drug layer may also comprise at least one polymerhydrogel. The polymer hydrogel may have an average molecular weight ofbetween about 500 and about 6,000,000. Examples of polymer hydrogelsinclude but are not limited to a maltodextrin polymer comprising theformula (C₆ H₁₂ O₅)_(n).H₂O, wherein n is 3 to 7,500, and themaltodextrin polymer comprises a 500 to 1,250,000 number-averagemolecular weight; a poly(alkylene oxide) represented by, e.g., apoly(ethylene oxide) and a poly(propylene oxide) having a 50,000 to750,000 weight-average molecular weight, and more specificallyrepresented by a poly(ethylene oxide) of at least one of 100,000,200,000, 300,000 or 400,000 weight-average molecular weights; an alkalicarboxyalkylcellulose, wherein the alkali is sodium or potassium, thealkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000weight-average molecular weight; and a copolymer of ethylene-acrylicacid, including methacrylic and ethacrylic acid of 10,000 to 500,000number-average molecular weight.

In certain embodiments of the present invention, the delivery or pushlayer comprises an osmopolymer. Examples of an osmopolymer include butare not limited to a member selected from the group consisting of apolyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxidepossesses a 1,000,000 to 10,000,000 weight-average molecular weight. Thepolyalkylene oxide may be a member selected from the group consisting ofpolymethylene oxide, polyethylene oxide, polypropylene oxide,polyethylene oxide having a 1,000,000 average molecular weight,polyethylene oxide comprising a 5,000,000 average molecular weight,polyethylene oxide comprising a 7,000,000 average molecular weight,cross-linked polymethylene oxide possessing a 1,000,000 averagemolecular weight, and polypropylene oxide of 1,200,000 average molecularweight. Typical osmopolymer carboxyalkylcellulose comprises a memberselected from the group consisting of alkali carboxyalkylcellulose,sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodiumcarboxyethylcellulose, lithium carboxymethylcellulose, sodiumcarboxyethylcellulose, carboxyalkylhydroxyalkylcellulose,carboxymethylhydroxyethyl cellulose, carboxyethylhydroxyethylcelluloseand carboxymethylhydroxypropylcellulose. The osmopolymers used for thedisplacement layer exhibit an osmotic pressure gradient across thesemipermeable wall. The osmopolymers imbibe fluid into dosage form,thereby swelling and expanding as an osmotic hydrogel (also known asosmogel), whereby they push the oxycodone or pharmaceutically acceptablesalt thereof from the osmotic dosage form.

The push layer may also include one or more osmotically effectivecompounds also known as osmagents and as osmotically effective solutes.They imbibe an environmental fluid, for example, from thegastrointestinal tract, into dosage form and contribute to the deliverykinetics of the displacement layer. Examples of osmotically activecompounds comprise a member selected from the group consisting ofosmotic salts and osmotic carbohydrates. Examples of specific osmagentsinclude but are not limited to sodium chloride, potassium chloride,magnesium sulfate, lithium phosphate, lithium chloride, sodiumphosphate, potassium sulfate, sodium sulfate, potassium phosphate,glucose, fructose and maltose.

The push layer may optionally include a hydroxypropylalkylcellulosepossessing a 9,000 to 450,000 number-average molecular weight. Thehydroxypropylalkylcellulose is represented by a member selected from thegroup consisting of hydroxypropyl-methylcellulose,hydroxypropylethylcellulose, hydroxypropylisopropylcellulose,hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose.

The push layer optionally may comprise a nontoxic colorant or dye.Examples of colorants or dyes include but are not limited to Food andDrug Administration Colorant (FD&C), such as FD&C No. 1 blue dye, FD&CNo. 4 red dye, red ferric oxide, yellow ferric oxide, titanium dioxide,carbon black, and indigo.

The push layer may also optionally comprise an antioxidant to inhibitthe oxidation of ingredients. Some examples of antioxidants include butare not limited to a member selected from the group consisting ofascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixtureof 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene,sodium isoascorbate, dihydroguaretic acid, potassium sorbate, sodiumbisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,vitamin E, 4-chloro-2,6-ditertiary butylphenol, alphatocopherol, andpropylgallate.

In certain alternative embodiments, the dosage form comprises ahomogenous core comprising oxycodone or a pharmaceutically acceptablesalt thereof, a pharmaceutically acceptable polymer (e.g., polyethyleneoxide), optionally a disintegrant (e.g., polyvinylpyrrolidone),optionally an absorption enhancer (e.g., a fatty acid, a surfactant, achelating agent, a bile salt, etc.). The homogenous core is surroundedby a semipermeable wall having a passageway (as defined above) for therelease of the oxycodone or pharmaceutically acceptable salt thereof.

In certain embodiments, the semipermeable wall comprises a memberselected from the group consisting of a cellulose ester polymer, acellulose ether polymer and a cellulose ester-ether polymer.Representative wall polymers comprise a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tricellulose alkenylates, and mono-, di- andtricellulose alkinylates. The poly(cellulose) used for the presentinvention comprises a number-average molecular weight of 20,000 to7,500,000.

Additional semipermeable polymers for the purpose of this inventioncomprise acetaldehyde dimethycellulose acetate, cellulose acetateethylcarbamate, cellulose acetate methylcarbamate, cellulose diacetate,propylcarbamate, cellulose acetate diethylaminoacetate; semipermeablepolyamide; semipermeable polyurethane; semipermeable sulfonatedpolystyrene; semipermeable cross-linked polymer formed by thecoprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,876;semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; semipermeable crosslinked polystyrenes; semipermeablecross-linked poly(sodium styrene sulfonate); semipermeable crosslinkedpoly(vinylbenzyltrimethyl ammonium chloride); and semipermeable polymerspossessing a fluid permeability of 2.5×10⁻⁸ to 2.5×10⁻² (cm²/hr·atm)expressed per atmosphere of hydrostatic or osmotic pressure differenceacross the semipermeable wall. Other polymers useful in the presentinvention are known in the art in U.S. Pat. Nos. 3,845,770; 3,916,899and 4,160,020; and in Handbook of Common Polymers, Scott, J. R. and W.J. Roff, 1971, CRC Press, Cleveland, Ohio.

In certain embodiments, preferably the semipermeable wall is nontoxic,inert, and it maintains its physical and chemical integrity during thedispensing life of the drug. In certain embodiments, the dosage formcomprises a binder. An example of a binder includes, but is not limitedto a therapeutically acceptable vinyl polymer having a 5,000 to 350,000viscosity-average molecular weight, represented by a member selectedfrom the group consisting of poly-n-vinylamide, poly-n-vinylacetamide,poly(vinyl pyrrolidone), also known as poly-n-vinylpyrrolidone,poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, andpoly-n-vinyl-pyrrolidone copolymers with a member selected from thegroup consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinylfluoride, vinyl butyrate, vinyl laureate, and vinyl stearate. Otherbinders include for example, acacia, starch, gelatin, andhydroxypropylalkylcellulose of 9,200 to 250,000 average molecularweight.

In certain embodiments, the dosage form comprises a lubricant, which maybe used during the manufacture of the dosage form to prevent sticking todie wall or punch faces. Examples of lubricants include but are notlimited to magnesium stearate, sodium stearate, stearic acid, calciumstearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid,sodium stearyl fumarate, and magnesium palmitate.

In certain preferred embodiments, the present invention includes atherapeutic composition comprising 1 to 640 mg of the oxycodone orpharmaceutically acceptable salt thereof, 25 to 500 mg of poly(alkyleneoxide) having a 150,000 to 500,000 average molecular weight, 1 to 50 mgof poly(vinylpyrrolidone) having a 40,000 average molecular weight, and0 to about 7.5 mg of a lubricant.

In certain embodiments, the invention also provides a method foradministering 1 to 640 mg of oxycodone or a pharmaceutically acceptablesalt thereof by admitting orally 1 to 640 mg of oxycodone orpharmaceutically acceptable salt thereof to a patient administered froma dosage form comprising a semipermeable wall permeable toaqueous-biological fluid and impervious to the passageway of oxycodoneor pharmaceutically acceptable salt thereof, which semipermeable wallsurrounds an internal space comprising an oxycodone drug composition anda push composition, said oxycodone drug composition comprising 1 to 640mg of oxycodone or pharmaceutically acceptable salt thereof, 25 to 500mg of a poly(alkylene oxide) having a 150,000 to 500,000 averagemolecular weight, 1 to 50 mg of a poly(vinylpyrrolidone) having a 40,000average molecular weight, and 0 to 7.5 mg of a lubricant, said pushcomposition comprising 15 to 250 mg of a poly(alkylene oxide) of3,000,000 to 7,500,000 average molecular weight, 0 to 75 mg of anosmagent, 1 to 50 mg of a hydroxyalkylcellulose, 0 to 10 mg of ferricoxide, 0 to 10 mg of a lubricant, and 0 to 10 mg of antioxidant; and apassageway in the semipermeable wall for delivering the oxycodone orpharmaceutically acceptable salt thereof from the dosage form, byimbibing fluid through the semipermeable wall into the dosage formcausing the oxycodone or oxycodone salt composition to becomedispensable and the push composition to expand and push the oxycodone oroxycodone salt composition through the passageway, whereby through thecombined operations of the dosage form, the oxycodone or oxycodone saltis delivered at a therapeutically effective dose at a rate controlledover a sustained period of time.

The dosage forms of the present invention may optionally be coated withone or more coatings suitable for the regulation of release or for theprotection of the formulation. In one embodiment, coatings are providedto permit either pH-dependent or pH-independent release, e.g., whenexposed to gastrointestinal (GI) fluid. When a pH-independent coating isdesired, the coating is designed to achieve optimal release regardlessof pH-changes in the environmental fluid, e.g., the GI tract. Otherpreferred embodiments include a pH-dependent coating that releases theoxycodone or pharmaceutically acceptable salt thereof in desired areasof the GI tract, e.g., the stomach or small intestine, such that anabsorption profile is provided which is capable of providing at leastabout twelve hours and preferably about twenty-four hours or more ofanalgesia to a patient. It is also possible to formulate compositionswhich release a portion of the dose in one desired area of the GI tract,e.g., the stomach, and release the remainder of the dose in another areaof the GI tract, e.g., the small intestine.

Formulations according to the invention that utilize pH-dependentcoatings may also impart a repeat-action effect whereby unprotected drugis coated over an enteric coat and is released in the stomach, while theremainder, being protected by the enteric coating, is released furtherdown the gastrointestinal tract. Coatings which are pH-dependent and maybe used in accordance with the present invention include a sustainedrelease material such as, e.g., shellac, cellulose acetate phthalate(CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulosephthalate, and methacrylic acid ester copolymers, zein, and the like.

In certain embodiments of the present invention, an effective amount ofoxycodone or pharmaceutically acceptable salt thereof in immediaterelease form is included in the formulation. The immediate release formof the oxycodone or oxycodone salt is included in an amount which iseffective to reduce the time to maximum concentration of the oxycodonein the blood (e.g., plasma), such that the T_(max) is reduced. Byincluding such an effective amount of immediate release oxycodone oroxycodone salt in the unit dose, the experience of relatively higherlevels of pain in patients may be reduced. In such embodiments, aneffective amount of the oxycodone or oxycodone salt in immediate releaseform may be coated onto the tablet of the present invention. Forexample, where the extended release oxycodone or oxycodone salt from theformulation is due to a sustained release coating, the immediate releaselayer would be overcoated on top of the sustained release coating. Onthe other hand, the immediate release layer may be coated onto thesurface of tablets wherein the oxycodone or oxycodone salt isincorporated in a sustained release matrix. One skilled in the art wouldrecognize still other alternative manners of incorporating the immediaterelease oxycodone or oxycodone salt portion into the formulation. Suchalternatives are deemed to be encompassed by the appended claims.

In yet further embodiments, the sustained release dosage forms of thepresent invention in addition to oxycodone or oxycodone salt may furtherinclude a non-opioid drug which may or may not act synergistically withthe oxycodone or oxycodone salt. Such non-opioid drugs would preferablyprovide additional analgesia, and include, for example, aspirin;acetaminophen; non-steroidal anti-inflammatory drugs (“NSAIDS”), e.g.,ibuprofen, ketoprofen, etc.; N-methyl-D-aspartate (NMDA) receptorantagonists, e.g., a morphinan such as dextromethorphan or dextrorphan,or ketamine; cyclooxygenase-II inhibitors (“COX-II inhibitors”); and/orglycine receptor antagonists.

In certain embodiments of the present invention, the invention allowsfor the use of lower doses of oxycodone or oxycodone salt by virtue ofthe inclusion of an additional non-opioid analgesic, such as an NSAID ora COX-2 inhibitor. By using lower amounts of either or both drugs, theside effects associated with effective pain management in humans may bereduced.

Suitable non-steroidal anti-inflammatory agents, include ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam,pharmaceutically acceptable salts thereof, mixtures thereof, and thelike. Useful dosages of these drugs are well known to those skilled inthe art.

N-methyl-D-aspartate (NMDA) receptor antagonists are well known in theart, and encompass, for example, morphinans such as dextromethorphan ordextrorphan, ketamine, or pharmaceutically acceptable salts thereof. Forpurposes of the present invention, the term “NMDA antagonist” is alsodeemed to encompass drugs that at least partially inhibit a majorintracellular consequence of NMDA-receptor activation, e.g. aganglioside such as GM₁ or GT_(1b), a phenothiazine such astrifluoperazine or a naphthalenesulfonamide such asN-(6-aminothexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g., narcotic analgesics such as morphine, codeine,etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et al.),and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.).The NMDA antagonist may be included alone, or in combination with alocal anesthetic such as lidocaine, as described in these Mayer, et al.patents.

The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,680 (Weber, et al.).

COX-2 inhibitors have been reported in the art and many chemicalstructures are known to produce inhibition of cyclooxygenase-2. COX-2inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995;5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and5,130,311. Certain preferred COX-2 inhibitors include celecoxib(SC-58635), DUP-697, flosulide (CGP-28238), meloxicam, 6-methoxy-2naphthylacetic acid (6-MNA), MK-966 (also known as Vioxx), nabumetone(prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614; orcombinations thereof. Dosage levels of COX-2 inhibitor on the order offrom about 0.005 mg to about 140 mg per kilogram of body weight per dayare therapeutically effective in combination with oxycodone or oxycodonesalt. Alternatively, about 0.25 mg to about 7 g per patient per day of aCOX-2 inhibitor is administered in combination with oxycodone oroxycodone salt.

In yet further embodiments, a non-opioid drug can be included whichprovides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, antihistamine drugs, local anesthetics, andthe like.

The additional (non-opioid) therapeutically active agent may be includedin sustained release form or in immediate release form. The additionaldrug may be incorporated into the sustained release matrix along withthe oxycodone or oxycodone salt, may be incorporated as a powder,granulation, etc. into the dosage form, or may be incorporated as aseparated sustained release layer or immediate release layer.

The sustained-release oral solid dosage forms of the present inventionmay be opioid-sparing. It is possible that the sustained-release oralsolid dosage forms of the present invention may be dosed at asubstantially lower daily dosage in comparison to conventionalimmediate-release products, with no significant difference in analgesicefficacy. At comparable daily dosages, greater efficacy may result withthe use of sustained-release oral solid dosage forms of the presentinvention in comparison to conventional immediate-release products.

The present invention will now be more fully described with reference tothe accompanying examples. It should be understood, however, that thefollowing description is illustrative only and should not be taken inany way as a restriction on the generality of the invention specifiedabove.

EXAMPLE 1

Oxycodone sustained release matrix tablets are produced with the formulaset forth in Table 1 below:

TABLE 1 Amt/unit Amt/batch Ingredient (mg) (gram) Oxycodone HCl 30.0150.0 Spray Dried Lactose 50.0 250.0 Povidone 8.0 40.0 Eudragit RS30D(Solids) 50.0 250.0 Triacetin 6.0 30.0 Stearyl Alcohol 70.0 350.0 Talc4.0 20.0 Magnesium Stearate 2.0 10.0 Opadry Red YS1-15597-A 10.0 50.0Purified Water * * Total 230.0 1150.0 * Used for processing and remainsin product as residual moisture only.

According to the following procedure:

-   -   1. Granulation: Spray the Eudragit/Triacetin dispersion onto the        Oxycodone HCl, Spray Dried Lactose and Povidone using a fluid        bed granulator.    -   2. Milling: Discharge the granulation and pass through a mill        with approximately 1 mm openings (18 mesh screen).    -   3. Waxing: Melt the stearyl alcohol at about 50 degrees C. and        add to the milled granulation using a high shear mixer. Allow to        cool to room temperature on trays or a fluid bed.    -   4. Milling: Pass the cooled granulation through a mill with an        approximately 18 mesh screen.    -   5. Lubrication: Lubricate the granulation with talc and        magnesium stearate using a mixer.    -   6. Compression: Compress the granulation into tablets using a        Kilian® Tablet press.    -   7. Film Coating: Apply an aqueous film coat to the tablets using        a rotary pan.

EXAMPLE 2

Oxycodone sustained release osmotic tablets are produced with theformula set forth in Table 2 below:

TABLE 2 Ingredient Amt/unit (mg) Drug Layer: Oxycodone HCl 35.20Polyethylene oxide 130.24 Povidone 8.8 Magnesium Stearate 1.76Displacement Layer: Polyethylene oxide 85.96 Sodium chloride 40.50Hydroxypropylmethylcellulose 6.75 Ferric Oxide 1.35 Magnesium Stearate0.34 BHT 0.10 Semipermeable Wall: Cellulose acetate 38.6

The dosage form having the above formulation is prepared according tothe following procedure:

First, 175 g of oxycodone hydrochloride, 647.5 g of poly(ethylene oxide)possessing a 200,000 average molecular weight, and 43.75 g ofpoly(vinylpyrrolidone) having a 40,000 average molecular weight is addedto a mixer and mixed for 10 minutes. Then, 331 g of denatured anhydrousalcohol is added to the blended materials with continuous mixing for 10minutes. Then, the wet granulation is passed through a 20 mesh screen,allowed to dry at room temperature for 20 hours, and then passed througha 16 mesh screen. Next, the granulation is transferred to the mixer,mixed and lubricated with 8.75 g of magnesium stearate.

Then, the displacement or push composition for pushing the oxycodone HClcomposition from the dosage form is prepared as follows: first 3910 g ofhydroxypropylmethylcellulose possessing an 11,200 average molecularweight is dissolved in 45,339 g of water. Then, 101 g of butylatedhydroxytoluene is dissolved in 650 g of denatured anhydrous alcohol.Next, 2.5 kg of the hydroxypropylmethylcellulose aqueous solution isadded with continuous mixing to the butylated hydroxytoluene alcoholsolution. Then, binder solution preparation is completed by adding withcontinuous mixing the remaining hydroxypropylmethylcellulose aqueoussolution to the butylated hydroxytoluene alcohol solution.

Next, 36,000 g of sodium chloride is sized using a Quadro Comil® millequipped with a 21 mesh screen. Then, 1200 g of ferric oxide is passedthrough a 40 mesh screen. Then, the screened materials, 76,400 g ofpharmaceutically acceptable poly(ethylene oxide) possessing a 7,500,000average molecular weight, 2500 g of hydroxypropylmethylcellulose havinga 11,200 average molecular weight are added to a Glatt® Fluid BedGranulation's bowl. The bowl is attached to the granulator and thegranulation process is initiated for effecting granulation. Next, thedry powders are air suspended and mixed for 10 minutes. Then, the bindersolution is sprayed from 3 nozzles onto the powder. The granulating ismonitored during the process as follows: total solution spray rate of800 g/min; inlet temperature 43° C. and air flow 4300 m³/hr. At the endof solution spraying, 45,033 g, the resultant coated granulatedparticles are subjected to a drying process for 35 minutes.

The coated granules are sized using a Quadro Comil® mill with an 8 meshscreen. The granulation is transferred to a Tote® Tumbler, mixed andlubricated with 281.7 g of magnesium stearate.

Next, the drug composition comprising the oxycodone hydrochloride andthe push composition are compressed into bilayer tablets on a Kilian®Tablet press. First, 176 mg of the oxycodone hydrochloride compositionis added to the die cavity and precompressed, then, 135 mg of the pushcomposition is added and the layers are pressed under a pressure head of3 metric tons into an 11/32 inch (0.873 cm) diameter contacting layerarrangement.

The bilayered arrangements are coated with a semipermeable wall. Thewall forming composition comprises 100% cellulose acetate having a 39.8%acetyl content. The wall-forming composition is dissolved inacetone:water (95:5 wt:wt) cosolvent to make a 4% solid solution. Thewall-forming composition is sprayed onto and around the bilayers in a 24inch (60 cm) Vector® Hi-Coater. Next, one 20 mil (0.508 mm) exitpassageway is drilled through the semipermeable wall to connect the drugoxycodone layer with the exterior of the dosage form. The residualsolvent is removed by drying for 72 hours at 45EC and 45% humidity.Next, the osmotic dosage systems are dried for 4 hours at 45EC to removeexcess moisture. The dosage forms produced by this manufacture comprises35.20 mg of oxycodone HCl, 130.24 mg of poly(ethylene oxide) of 200,000average molecular weight, 8.80 mg of polyvinylpyrrolidone) of 40,000average molecular weight, and 1.76 mg of magnesium stearate. The pushcomposition comprises 85.96 mg of poly(ethylene oxide) of 7,500,000average molecular weight, 40.50 mg of sodium chloride, 6.75 mg ofhydroxypropylmethylcellulose, 1.35 mg of red ferric oxide, 0.34 mg ofmagnesium stearate, and 0.10 mg of butylated hydroxytoluene. Thesemipermeable wall comprises 38.6 mg of cellulose acetate comprising a39.8% acetyl content. The dosage form comprises one passageway, 20 mil(0.508 mm).

EXAMPLE 3

Oxycodone sustained release osmotic tablets are produced with theformula set forth in Table 3 below:

TABLE 3 Ingredient Percentage Drug Layer: Percentage of Drug LayerOxycodone HCL 28.8 Polyethylene oxide 64.2 Povidone 6 Magnesium Stearate1 Percentage of Displacement Displacement Layer: Layer Polyethyleneoxide 63.675 Sodium chloride 30 Hydroxypropylmethylcellulose 5 FerricOxide 1 Magnesium Stearate 0.25 BHT 0.075 Percentage of SemipermeableWall: Semipermeable Wall Cellulose acetate 95 Polyethylene glycol 5

The dosage form having the above formulation is prepared according tothe following procedure:

First, 1728 g of oxycodone HCl, 3852 g of poly(ethylene oxide)possessing a 200,000 average molecular weight, and 360 g of poly(vinylpyrrolidone) having an average molecular weight of 40,000 are added to aplanetary mixing bowl. Next, the dry materials are mixed for tenminutes. Then, 1616 g of denatured anhydrous ethyl alcohol is slowlyadded to the blended materials with continuous mixing for 15 minutes.Next, the freshly prepared wet granulation is passed through a 20 meshscreen, allowed to dry at room temperature for 20.5 hours, and passedthrough a 16 mesh screen. Next, the granulation is transferred to aplanetary mixer, mixed and lubricated with 59.8 g of magnesium stearate.

Next, a push composition is prepared as follows: first, a bindersolution is prepared by dissolving 3910 g ofhydroxypropylmethylcellulose possessing an average molecular weight of11,200 in 45,339 g of water. Next, 101 g of butylated hydroxytoluene isdissolved in 650 g of denatured anhydrous alcohol. Approximately 2.5 kgof the hydroxypropyl-methylcellulose/water solution is added to thebutylated hydroxytoluene/alcohol solution with continuous mixing. Next,the binder solution preparation is completed by adding the remaininghydroxypropyl-methylcellulose/water solution to the butylatedhydroxyl-toluene/alcohol solution, again with continuous mixing.

Next, 36,000 g of sodium chloride is sized using a Quadro Comil® mill,used to reduce the particle size of the sodium chloride. A fluid airmill is another mill used to size materials with a 21 mesh screen. Next,1200 g of ferric oxide is passed through a 40 mesh screen. Then, all thescreened materials, 76,400 g of pharmaceutically acceptablepoly(ethylene oxide) comprising a 7,000,000 average molecular weight,2520 g of hydroxypropylmethylcellulose comprising an average molecularweight of 11,200 is added to a Glatt Fluid Bed Granulator bowl. The bowlis attached to the granulator and the granulation process is initiatedfor effecting granulation. Next, the dry powders are air suspended andmixed for 10 minutes. Then, the binder solution is sprayed from 3nozzles onto the powder.

While spraying the binder solution, the filter bags are shaken for 10seconds every 1.5 minutes to unglue any possible powder deposits. At theend of the solution spraying, 45,033 g of the resultant coatedgranulated particles are subjected to a drying process for 35 minutes.The machine is turned off, and the coated granules are removed from thegranulator. The coated granules are sized using a Quadro Comil with an 8mesh screen. The granulation is transferred to Tote Tumbler, mixed andlubricated with 281.7 g of magnesium stearate. Please review secondsentence and clarify.

Next, the oxycodone HCl drug composition and the push composition arecompressed into bilayer tablets on the Kilian® Tablet Press. First, 434mg of the oxycodone HCl composition is added to the die cavity andpre-compressed, then, 260 mg of the push composition is added and thelayers are pressed under a pressure head of approximately 3 metric tonsinto a 0.700″ (1.78 cm)×0.375″ (0.95 cm) oval contacting layeredarrangement.

The bilayered arrangement is coated with a semi-permeable wall. The wallforming composition comprises 95% cellulose acetate having a 39.8%acetyl content, and 5% polyethylene glycol having a molecular weight of3350. The wall-forming composition is dissolved in an acetone:water(95:5 wt:wt) cosolvent to make a 4% solids solution. The wall-formingcomposition is sprayed onto and around the bilayers in a 24″ Vector Hi®Coater.

Next, two 30 mil (0.762 mm) exit passageways are drilled through thesemi-permeable wall to connect the drug layer with the exterior of thedosage system. The residual solvent is removed by drying for 48 hours at50EC and 50% humidity. Next, the osmotic dosage forms are dried for 4hours at 50EC to remove excess moisture. The dosage form produced bythis manufacture provides 28.8% oxycodone HCl, 64.2% poly(ethyleneoxide) possessing a 200,000 average molecular weight, 6% poly(vinylpyrrolidone) possessing a 40,000 average molecular weight, and 1%magnesium stearate. The push composition comprises 63.675% poly(ethyleneoxide) comprising a 7,000,000 average molecular weight, 30% sodiumchloride, 5% hydroxypropylmethylcellulose comprising a 11,200 averagemolecular weight, 1% ferric oxide, 0.075% butylated hydroxytoluene, and0.25% magnesium stearate. The semipermeable wall comprises 95 wt %cellulose acetate comprising a 39.8% acetyl content, and 5.0 wt %polyethylene glycol comprising a 3350 average molecular weight. Thedosage form comprises two passageways, 30 mils (0.762 mm), and has anoxycodone hydrochloride mean release rate of about 5 mg/hr.

The dosage form in further embodiments can comprise 65 wt % to 100 wt %of a cellulose polymer which polymer comprises a member selected fromthe group consisting of a cellulose ester, cellulose diester, cellulosetriester, cellulose ether, cellulose ester-ether, cellulose acylate,cellulose diacylate, cellulose triacetate, cellulose acetate butyrate,and the like. The wall can also comprise from 0 wt % to 40 wt % of acellulose ether member selected from the group consisting ofhydroxypropylcellulose and hydroxypropylmethylcellulose and from 0 wt %to 20 wt % of polyethylene glycol. The total amount of all componentscomprising the wall is equal to 100 wt %. Semipermeable polymers usefulfor manufacturing wall of the dosage form are disclosed in U.S. Pat.Nos. 3,845,770; 3,916,899; 4,008,719; 4,036,228; and 4,111,201.

The wall in other preferred processes comprises the selectivelypermeable cellulose ether, ethyl cellulose. The ethyl cellulosecomprises an ethoxy group with a degree of substitution, of about 1.4 to3, equivalent to 40% to 50% ethoxy content, and a viscosity range of 7to 100 centipoise, or higher. More specifically, the wall comprises 45wt % to 80 wt % ethyl cellulose, from 5 wt % to 30 wt %hydroxypropylcellulose, and from 5 wt % to 30 wt % polyethylene glycol,with the total weight percent of all components comprising the wallequal to 100 wt %. In another embodiment the wall comprises 45 wt % to80 wt % of ethylcellulose, from 5 wt % to 30 wt %hydroxypropylcellulose, from 2 wt % to 20 wt % of polyvinyl pyrrolidone,with the total amount of all components comprising the wall equal to 100wt %.

EXAMPLE 4

Oxycodone 10 mg sustained release capsules were prepared with theformula set forth in Table 4 below:

TABLE 4 Amt/unit Ingredient (mg) Oxycodone HCl 10.0 Stearic Acid 8.25Stearic Alcohol 24.75 Eudragit RSPO 77 Total 120

The formulation above was prepared according to the following procedure:

-   -   1. Pass the stearyl alcohol flakes through an impact mill.    -   2. Blend the Oxycodone HCl, stearic acid, stearyl alcohol and        the Eudragit RSPO in a suitable blender/mixer.    -   3. Continuously feed the blended material into a twin screw        extruder at elevated temperatures, and collect the resultant        strands on a conveyor.    -   4. Allow the strands to cool on the conveyor.    -   5. Cut the strands into 1 mm pellets using a pelletizer.    -   6. Screen the pellets for fines and oversized pellets to an        acceptable range of about 0.8-1.4 mm in size.    -   7. Fill into capsules with a fill weight of 120 mg/capsule (fill        into size 2 capsules).    -   The pellets were then tested for dissolution using the following        procedure: Fiber optic UV dissolution using USP apparatus 1        (basket) at 100 rpm in 900 ml simulated gastric fluid (SGF) and        in 900 ml simulated intestinal fluid (SIF) monitoring at 282 nm.

The dissolution parameters are set forth in Table 4A below:

TABLE 4A Time % Dissolved in % Dissolved in (hour) SGF SIF 1 15 10 2 2215 4 32 22 8 44 29 12 53 34 18 62 40 24 66 44

EXAMPLE 5

Oxycodone 160 mg sustained release capsules were prepared with theformula set forth in Table 5 below:

TABLE 5 Amt/unit Ingredient (mg) Oxycodone HCL 160 Stearic Acid 80Stearyl Alcohol 20 Eudragit RSPO 140 Total 400

The formulation above was prepared according to the following procedure:

-   1. Pass the stearyl alcohol flakes through an impact mill.-   2. Blend the Oxycodone HCl, stearic acid, stearyl alcohol and the    Eudragit RSPO in a suitable lender/mixer.-   3. Continuously feed the blended material into a twin screw extruder    at elevated temperatures and collect the resultant strands on a    conveyor.-   4. Allow the strands to cool on the conveyor.-   5. Cut the strands into 1 mm pellets using a pelletizer.-   6. Screen the pellets for fines and oversized pellets to an    acceptable range of about 0.8-1.4 mm in size.-   7. Fill into capsules with a fill weight of 400 mg/capsule (Fill    into size 00 capsules).    Dissolution Method:

The pellets were then tested for dissolution using the followingprocedure:

-   -   Fiber optic UV dissolution using USP apparatus 1 (basket) at 100        rpm in 900 ml simulated gastric fluid (SGF) and in 900 ml        simulated intestinal fluid (SIF) monitoring at 282 nm.    -   The dissolution parameters for the above formulation are set        forth in Table 5A below: Please ensure Table 5A does not have        error message.

TABLE 5A Time % Dissolved in % Dissolved in (hour) SGF SIF 1 32 20 2 4728 4 66 42 8 86 60 12 93 70 18 95 77 24 95 80

Many other variations of the present invention will be apparent to thoseskilled in the art and are meant to be within the scope of the claimsappended hereto.

What is claimed is:
 1. A sustained-release oral dosage form comprising:a plurality of units containing one or more active agents and one ormore excipients, wherein one of the active agents is oxycodone or apharmaceutically acceptable salt thereof, the excipients comprise asustained release material comprising ethylcellulose, a methacrylic acidcopolymer or a mixture thereof, the amount of the oxycodone orpharmaceutically acceptable salt thereof in the dosage form is fromabout 10 mg to about 320 mg, the dosage form provides a mean C₂₄/C_(max)oxycodone ratio of from 0.6 to 1.0 and a mean T_(max) of oxycodone ofabout 6.5 to about 17 hours after steady state oral administration withfood to humans, the dosage form is a capsule, and a diameter of eachunit is from about 0.1 mm to about 5 mm.
 2. The dosage form of claim 1,wherein the excipients are selected from the group consisting of (i) thesustained release material; (ii) cellulose ethers, (iii)hydroxyalkylcelluloses; (iv) plasticizers; (v) talc; and (vi)antioxidants.
 3. The dosage form of claim 1, wherein the dosage formprovides a mean C₂₄/C_(max) oxycodone ratio of about 0.7 to 0.99 afteradministration with food at steady state to said humans.
 4. The dosageform of claim 3, wherein the dosage form provides a mean C₂₄/C_(max)oxycodone ratio of 0.7 to 0.95 after administration with food at steadystate to said humans.
 5. The dosage form of claim 1, wherein the dosageform provides a mean T_(max) of oxycodone at about 8 to about 16 hoursafter administration with food at steady state to said humans.
 6. Asustained-release oral dosage form comprising a plurality of unitscomprising: oxycodone or a pharmaceutically acceptable salt thereof, asustained release material comprising ethylcellulose, a methacrylic acidcopolymer, a hydroxyalkylcellulose, or mixtures thereof, andplasticizers, the dosage form providing a mean C₂₄/C_(max) oxycodoneratio of 0.6 to 1.0 and a mean T_(max) of oxycodone of about 6.5 toabout 17 hours after steady state oral administration to humans, whereinthe amount of the oxycodone or pharmaceutically acceptable salt thereofin the dosage form is from about 10 mg to about 320 mg, the dosage formis a capsule, and a diameter of each unit is from about 0.1 mm to about5 mm.
 7. The dosage form of claim 6, providing a mean T_(max) ofoxycodone at about 8 to about 16 hours after administration at steadystate to said humans.
 8. The dosage form of claim 6, providing a meanT_(max) of oxycodone at about 10 to about 16 hours after administrationat steady state to said humans.
 9. The dosage form of claim 6, whereinplasticizers comprise diethyl phthalate.
 10. The dosage form of claim 6,providing a mean T_(max) of oxycodone at about 12 to about 16 hoursafter administration at steady state to said humans.
 11. The dosage formof claim 6, providing an analgesic effect for about 24 hours.
 12. Thedosage form of claim 6, providing a mean C₂₄/C_(max) oxycodone ratio of0.7 to 0.99 after administration at steady state to said humans.
 13. Thedosage form of claim 6, providing a mean C₂₄/C_(max) oxycodone ratio of0.8 to 0.95 after administration at steady state to said humans.
 14. Thedosage form of claim 6, providing an in-vitro release rate of oxycodone,when measured by the USP Basket Method at 100 rpm in 900 ml aqueousbuffer at a pH of between 1.6 and 7.2 at 37° C., such that from 0% toabout 40% of the oxycodone is released at 1 hour, from about 8% to about70% of the oxycodone is released at 4 hours, from about 20% to about 80%of the oxycodone is released at 8 hours, from about 30% to about 95% ofthe oxycodone is released at 12 hours, from about 35% to about 95% ofthe oxycodone is released at 18 hours, and greater than about 50% of theoxycodone is released at 24 hours.
 15. The dosage form of claim 6,wherein said oxycodone is coated with said sustained release materialand plasticizers.
 16. A sustained-release oral dosage form comprising: aplurality of units comprising oxycodone or a pharmaceutically acceptablesalt thereof, a methacrylic acid copolymer and polyethylene glycol,wherein the amount of the oxycodone or pharmaceutically acceptable saltthereof in the dosage form is from about 10 mg to about 320 mg, thedosage form provides a mean C₂₄/C_(max) oxycodone ratio of 0.6 to 1.0and a mean T_(max) of oxycodone of about 6.5 to about 17 hours aftersteady state oral administration with food to humans, the dosage form isa capsule, and a diameter of each unit is from about 0.1 mm to about 5mm.
 17. The dosage form of claim 16, wherein the amount of the oxycodoneor pharmaceutically acceptable salt thereof in the dosage form is fromabout 10 mg to about 160 mg.
 18. The dosage form of claim 16, whereinthe pharmaceutically acceptable salt of oxycodone is oxycodonehydrochloride.
 19. The dosage form of claim 16, wherein the dosage formprovides a mean T_(max) of oxycodone at about 8 to about 16 hours afteradministration with food at steady state to said humans.
 20. The dosageform of claim 16, wherein the dosage form provides a mean T_(max) ofoxycodone at about 10 to about 16 hours after administration with foodat steady state to said humans.
 21. The dosage form of claim 16, whereinthe dosage form provides an analgesic effect for about 24 hours.
 22. Thedosage form of claim 16, wherein the dosage form provides a meanC₂₄/C_(max) oxycodone ratio of about 0.7 to 0.99 after administrationwith food at steady state to said humans.
 23. The dosage form of claim16, wherein the dosage form provides a mean C₂₄/C_(max) oxycodone ratioof 0.7 to 0.95 after administration with food at steady state to saidhumans.
 24. The dosage form of claim 16, wherein the dosage formprovides an in-vitro release rate of oxycodone, when measured by the USPBasket Method at 100 rpm in 900 ml aqueous buffer at a pH of between 1.6and 7.2 at 37 ° C., such that from 0% to about 40% of the oxycodone isreleased at 1 hour, from about 8% to about 70% of the oxycodone isreleased at 4 hours, from about 20% to about 80% of the oxycodone isreleased at 8 hours, from about 30% to about 95% of the oxycodone isreleased at 12 hours, from about 35% to about 95% of the oxycodone isreleased at 18 hours, and greater than about 50% of the oxycodone isreleased at 24 hours.
 25. The dosage form of claim 16, wherein the unitscomprise talc.
 26. The dosage form of claim 1, wherein the dosage formprovides an in-vitro release rate of oxycodone, when measured by the USPBasket Method at 100 rpm in 900 ml aqueous buffer at a pH of between 1.6and 7.2 at 37 ° C., such that from 0% to about 40% of the oxycodone isreleased at 1 hour, from about 8% to about 70% of the oxycodone isreleased at 4 hours, from about 20% to about 80% of the oxycodone isreleased at 8 hours, from about 30% to about 95% of the oxycodone isreleased at 12 hours, from about 35% to about 95% at of the oxycodone isreleased at 18 hours, and greater than about 50% of the oxycodone isreleased at 24 hours.